KR100708783B1 - N-heterocyclic derivatives as NOS inhibitors - Google Patents

Abstract

Described herein are N-heterocyclic derivatives of Formula (Ya), and other N-heterocyclic compounds as nitric oxide synthase inhibitors. Also described herein are pharmaceutical compositions containing these compounds, methods of using these compounds as nitric oxide synthase inhibitors, and methods of synthesizing these compounds.

N-heterocyclic derivatives, nitric oxide synthase inhibitors

Description

N-Heterocyclic Derivatives as NOS Inhibitors

The present invention relates to a series of N-heterocyclic compounds and derivatives thereof useful as inhibitors of nitric oxide synthase (NOS), and methods of treating various diseases using these compounds.

Nitric oxide (NO) is involved in a variety of physiological processes, including smooth muscle relaxation, platelet inhibition, neurotransmission, immune regulation, and penile erection. Nitric oxide is produced under a variety of conditions by almost all mammalian cells with a nucleus. Many pathological conditions are believed to be due to abnormalities in NO production, including stroke, insulin dependent diabetes, septic shock-induced hypertension, rheumatoid arthritis and multiple sclerosis. Nitric oxide is synthesized in organisms by an enzyme called nitric oxide synthase (NOS), which produces citrulline and nitric oxide by oxidizing L-arginine with NADPH and oxygen molecules.

Nitric oxide synthase (NOS) exists in at least three isoforms, which are divided into two main categories: constitutive NOS and inducible NOS. Two constitutive isotypes dependent on calcium and calmodulin were identified, and one inducible isotype was identified. The constitutive isotypes are called (1) NOS-1 or nNOS, neuronal isoforms found in the brain and skeletal muscle, and (2) NOS-3 or eNOS and are expressed in the vascular endothelium, bronchial epithelium and brain. There is an endothelial isoform that becomes. These constitutive isotypes are not targets for the NOS inhibitors of the invention.

Inducible isotypes (NOS2 or iNOS) are expressed after exposure to inflammatory cytokines or lipopolysaccharides in almost all mammalian cells with nuclei. Of particular note is the presence of inducible isotypes in macrophages and lung epithelial cells. Inducible isotypes are neither stimulated by calcium nor blocked by calmodulin antagonists. Inducible isotypes are strongly bound to several cofactors including FMN, FAD and tetrahydrobiopterrin.

Nitric oxide produced by the inducible form of NOS is involved in the development of inflammatory diseases. In experimental animals, hypertension induced by lipopolysaccharide or tumor necrosis factor α can be cured by NOS inhibitors. Symptoms causing cytokine-induced hypertension include septic shock, hemodialysis and interleukin treatment in cancer patients. iNOS inhibitors are expected to be effective in the treatment of cytokine-induced hypertension. In addition, recent studies have suggested a role for NO in the development of inflammation, and therefore NOS inhibitors will have beneficial effects on inflammatory bowel disease, cerebral ischemia and arthritis. Inhibitors of NOS may be useful for treating adult respiratory distress syndrome (ARDS) and myocarditis, and may be useful as an adjuvant for short-term immunosuppression in transplantation therapy.

The diversity and ubiquity of NO in physiological action make certain therapeutic targeting of NO-related phenomena important. Because endogenous NO production is the result of the action of relevant but distinct isozymes, the differential inhibition of NOS isozyme has few side effects and enables more selective treatment.

<Overview of invention>

In one aspect, the invention relates to compounds of formula (Ya), formula (Yb) and formula (Yc) as single stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof.

Where

n and m are each independently an integer of 1 to 4,

A is -C (O) OR ¹ or -C (O) N (R ¹ ) R ² ,

W is N or CH, respectively,

Each R ¹ is independently hydrogen, alkyl, aryl or aralkyl,

Each R ² is independently hydrogen, C ₀ -C ₂₀ alkyl,-(CH ₂ ) _n -N (R ¹ ) ₂ , heterocyclylalkyl (optionally substituted by alkyl, halo, haloalkyl or alkoxy) Or aralkyl (which may be optionally substituted by halo, alkyl, alkoxy or -N (R ¹ ) ₂ ),

R ⁴ is hydroxy, cyano, heterocyclyl, -N (R ¹ ) R ² , -N (R ¹ ) -C (O) -R ¹ , -N (R ¹ ) -C (O) OR ¹ , -N (R ¹ ) -S (O) _t -R ¹ or -N (R ¹ ) -C (O) -N (R ¹ ) ₂ ,

R ⁵ is hydrogen, halo, alkyl, aryl, aralkyl or haloalkyl.

In another aspect, the invention relates to compounds of formula (IV) as single isomers or mixtures thereof, or as pharmaceutically acceptable salts thereof.

Where

AA is an amino acid,

X, Y and Z are independently N or C (R ¹⁹ ),

U is N or C (R ⁵ ) (where U is N only if X is N and Z and Y are CR ¹⁹ ),

W is N or CH,

R ¹ and R ² are independently hydrogen, optionally substituted C ₁ -C ₂₀ alkyl, optionally substituted cycloalkyl,-[C ₀ -C ₈ alkyl] -R ⁹ ,-[C ₂ -C ₈ Alkenyl] -R ⁹ ,-[C ₂ -C ₈ alkynyl] -R ⁹ ,-[C ₂ -C ₈ alkyl] -R ¹⁰ (optionally substituted by hydroxy),-[C _1- C ₈ ] -R ¹¹ (which may be optionally substituted by hydroxy), and optionally substituted heterocyclyl, or R ¹ and R ² are optionally substituted with the nitrogen atom to which they are attached Form N-heterocyclyl,

R ⁵ is hydrogen, halo, alkyl, haloalkyl, optionally substituted aralkyl, optionally substituted aryl, -OR ¹⁶ , -S (O) _t -R ¹⁶ , -N (R ¹⁶ ) R ²¹ , -N (R ¹⁶ ) C (O) N (R ¹ ) R ¹⁶ , -N (R ¹⁶ ) C (O) OR ¹⁶ , -N (R ¹⁶ ) C (O) R ¹⁶ ,-[C ₀ -C ₈ alkyl] -C (O) OR ¹⁶ ,-[C ₀ -C ₈ alkyl] -C (H) [C (O) OR ¹⁶ ] ₂ and-[C ₀ -C ₈ alkyl] -C (O) N (R ¹ ) R ¹⁶ is selected from the group consisting of

Each R ⁹ is independently optionally substituted by one or more substituents selected from the group consisting of haloalkyl, cycloalkyl (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (halo, alkyl and alkoxy) ), And heterocyclyl (which may be optionally substituted by alkyl, aralkyl or alkoxy),

Each R ¹⁰ is independently halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted -S (O) _t -R ²² , acylamino, amino, monoalkylamino, Dialkylamino, (triphenylmethyl) amino, hydroxy, mercapto, and alkylsulfonamido,

Each R ¹¹ is independently selected from the group consisting of cyano, di (alkoxy) alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl,

Each R ¹⁶ is independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or cycloalkyl,

R ¹⁹ is hydrogen, alkyl (which may be optionally substituted by hydroxy), cyclopropyl, halo or haloalkyl,

R ²¹ is hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, —C (O) R ²² or —SO ₂ R ^22, or R ²¹ is attached to R ¹ and themselves Together with nitrogen forms N-heterocyclyl which may be optionally substituted, or R ²¹ forms with R ¹⁶ and optionally attached N-heterocyclyl,

Each R ²² is independently alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl,

t is 0, 1 or 2.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (Ya), formula (Yb) and formula (Yc) as described above, and a pharmaceutically acceptable carrier.

In another aspect, the invention comprises administering an effective amount of the above formulas (Ya), (Yb) and (Yc) compounds to a mammal suffering from a condition arising from abnormalities in nitric oxide production. The present invention relates to a method for treating a symptom that develops from abnormalities in production.

Justice

The following terms used in the specification and the appended claims have the following meanings unless specifically indicated otherwise.

"Alkyl" means a straight or branched chain hydrocarbon group consisting only of carbon and hydrogen atoms, free from unsaturated bonds, containing from 1 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond; Examples include methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-phenyl and 1,1-dimethylethyl (t-butyl). Alkyl groups containing more than eight carbon atoms are _denoted herein by the symbol “[C _x -C _y alkyl]” where x and y represent the number of carbons present. Alkyl groups are halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, nitro, alkylthio, amidino, aryl, heterocyclyl, aryloxy, aralkoxy And optionally substituted by one or more substituents independently selected from the group consisting of acylamino, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl.

"Alkenyl" refers to a straight or branched monovalent or divalent group consisting of only carbon and hydrogen, containing at least one double bond and containing from 1 to 8 carbon atoms, e.g. Tenyl, prop-1-enyl, but-1-enyl, pent-1-enyl and penta-1,4-dienyl and the like.

"Alkynyl" refers to a straight or branched monovalent or divalent group consisting of only carbon and hydrogen, containing one or more triple bonds and containing from 1 to 8 carbon atoms, e.g. Tinyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl and pent-3-ynyl.

"Alkoxy" means a group of the formula -OR _a where R _a is an alkyl group as defined above, and examples thereof include methoxy, ethoxy, propoxy and the like.

"Alkoxycarbonyl" means a group of the formula -C (O) OR _a where R _a is an alkyl group as defined above, examples being methoxycarbonyl, ethoxycarbonyl and n-propoxycarbonyl Etc.

"Alkoxycarbonylalkyl" means a group of the formula -R _a -C (O) OR _a where R _a is independently an alkyl group as defined above, for example 2- (methoxycarbonyl) ethyl, 3- (ethoxycarbonyl) propyl and 4- (n-propoxycarbonyl) butyl and the like.

"Alkylsulfonylamino" means a group of the formula -N (H) S (O) ₂ -R _a , wherein R _a is an alkyl group as defined above, examples being methylsulfonylamino and ethylsulfonylamino Etc.

"Alkylsulfonyl" means a group of the formula -S (O) ₂ -R _a , wherein R _a is an alkyl group as defined above, examples include methylsulfonyl, ethylsulfonyl, and the like.

"Alkylthio" means a group of the formula -SR _a where R _a is an alkyl group as defined above, examples include methylthio, ethylthio, n-propylthio and the like.

"Amidino" means a group of the formula -C (NH) -NH ₂ .

"Amino" means a group of the formula -NH ₂ .

"Aminocarbonyl" means a group of the formula -C (O) NH ₂ .

"Aminosulfonyl" means a group of the formula -S (O) ₂ NH ₂ .

"Aryl" means a phenyl group or a naphthyl group. Aryl groups are hydroxy, mercapto, halo, alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, phenylalkenyl, alkoxy, phenoxy, phenylalkoxy, haloalkyl, haloalkoxy, formyl, as defined herein. , Nitro, cyano, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amidino, ureido, alkoxycarbonylamino, amino, monoalkylamino, dialkylamino, monophenylamino, mono Phenylalkylamino, sulfonylamino, alkylsulfonylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monophenylaminoalkyl, monophenylalkylaminoalkyl, acyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl , Monoalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl and dialkylaminocarbonylalkyl Optionally substituted by one or more substituents.

"Aralkyl" means a group of the formula -R _a R _b , wherein R _a is an alkyl group as defined above and R _b is an aryl group as defined above, for example benzyl and the like. Aryl groups may be optionally substituted as described above.

"Aryloxy" means a group of the formula -OR _b , wherein R _b is an aryl group as defined above, examples include phenoxy and naphthoxy, and the like. Aryl groups may be optionally substituted as described above.

"Aryloxycarbonyl" means a group of the formula -C (O) OR _b , wherein R _b is an aryl group as defined above, for example phenoxycarbonyl and the like.

"Aralkoxy" means a group of the formula -OR _c , wherein R _c is an aralkyl group as defined above, for example benzyloxy and the like. Aralkyl groups may be optionally substituted as described above.

“Aralkoxycarbonyl” means a group of the formula —C (O) OR _c , wherein R _c is an aralkyl group as defined above, for example benzyloxycarbonyl and the like. Aralkyl groups may be optionally substituted as described above.

"Arylaminocarbonyl" refers to a group of the formula -C (O) N (R _b ) H where R _b is an aryl group as defined above, for example phenylaminocarbonyl and the like. Aryl groups may be optionally substituted as described above.

"Arylaminosulfonyl" means a group of the formula -S (O) ₂ N (R _b ) H, wherein R _b is an aryl group as defined above, for example phenylaminosulfonyl and the like. Aryl groups may be optionally substituted as described above.

"Arylsulfonyl" means a group of the formula -S (O) ₂ -R _b , wherein R _b is an aryl group as defined above, for example phenylsulfonyl and the like. Aryl groups may be optionally substituted as described above.

"Arylsulfonylaminocarbonyl" means a group of the formula -C (O) N (H) S (O) ₂ R _b , wherein R _b is an aryl group as defined above, for example phenylsulfonylamino Carbonyl and the like. Aryl groups may be optionally substituted as described above.

"Acyl" means a group of the formula -C (O) -R _a and -C (O) R _b , wherein R _a is an alkyl group as defined above and R _b is an aryl group as defined above, for example acetyl , Propionyl and benzoyl.

"Acylamino" refers to the formulas -N (H) -C (O) -R _a and -N (H) -C (O) -R _b , wherein R _a is an alkyl group as defined above and R _b is as defined above Aryl group), and examples thereof include acetylamino and benzoylamino.

"Alkylene" is a straight or branched divalent group consisting only of carbon and hydrogen atoms, meaning a group having no unsaturated bonds and containing from 1 to 8 carbon atoms, for example methylene, ethylene, propylene and n Butylene and the like. Alkylene groups are alkyl, hydroxy, -N (R ¹⁶ ) R ²¹ or -C (O) N (R ¹ ) R ¹⁶ , wherein R ¹ , R ¹⁶ and R ²¹ are as defined in the Summary of the Invention. It may be optionally substituted by one or more substituents selected from the group consisting of.

"Cycloalkyl" is a stable 3- to 10-membered saturated monocyclic or bicyclic group consisting solely of carbon and hydrogen atoms, examples being cyclopropyl, cyclobutyl, cyclohexyl, decalinyl and the like have. Unless stated otherwise in the specification, the term "cycloalkyl" is optionally selected by one or more substituents independently selected from the group consisting of alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl It is meant to include a cycloalkyl group which may be substituted.

"Carboxy" means a group of the formula -C (O) OH.

"Carboxyalkyl" means a group of the formula -R _a -C (O) OH, wherein R _a is an alkyl group as defined above, for example carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like. .

“Di (alkoxy) alkyl” is of the formula —R _a (—OR _a ) ₂ , wherein R _a is each independently an alkyl group as defined above and the —OR _a group may be attached to any carbon in the R _a group Group, and examples thereof include 3,3-dimethoxypropyl and 2,3-dimethoxypropyl.

"Dialkylamino" means a group of the formula -N (R _a ) R _a , wherein R _a is each independently an alkyl group as defined above, for example dimethylamino, diethylamino and (methyl) (ethyl ) Amino and the like.

"Dialkylaminocarbonyl" means a group of the formula -C (O) N (R _a ) R _a , wherein R _a is each independently an alkyl group as defined above, for example dimethylaminocarbonyl, Methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl and the like.

"Dialkylaminosulfonyl" means a group of the formula -S (O) ₂ N (R _a ) R _a , wherein R _a is each independently an alkyl group as defined above, for example dimethylaminosulfonyl, Methylethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfonyl, ethylpropylaminosulfonyl and the like.

"Halo" means bromo, chloro, iodo or fluoro.

"Haloalkyl" means the alkyl group substituted by one or more halo groups as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 -Fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

"Haloalkoxy" means a group of the formula -OR _d where R _d is a haloalkyl group as defined above, for example trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2- Trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy and 1-bromomethyl-2-bromoethoxy.

"Heterocyclyl" is a stable 3- to 15-membered group consisting of carbon atoms and 1 to 5 heteroatoms (selected from the group consisting of nitrogen, oxygen and sulfur). For the purposes of the present invention, the heterocyclyl group may be a monocyclic, bicyclic or tricyclic ring system comprising a fused ring system or a bridged ring system; Nitrogen, carbon or sulfur atoms of the heterocyclyl group may be oxidized; The nitrogen atom may be optionally quaternized; Heterocyclyl groups may be partially or fully saturated or aromatic. Heterocyclyl groups can be bonded to any heteroatom or carbon atom of the main structure to produce a stable compound. Examples of such heterocyclyl groups include azepinyl, azetidinyl, acridinyl, benzimidazolyl, benzodioxolyl, benzodioxanyl, benzothiazolyl, benzoxazolyl, benzopyranyl, benzofuranyl, benzo Thienyl, carbazolyl, cinnolinyl, decahydroisoquinolyl, dioxolanyl, furyl, isothiazolyl, quinuclidinyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, Indolyl, isoindolinyl, indolinyl, isoindolinyl, indolinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadizolyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazinyl, oxazolyl, oxazolidinyl, perhydroazinyl, piperidinyl, piperazinyl, 4 Piperidonyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pterridinyl, furinyl, Rollyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl , Thiazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydroisoquinolyl, thienyl, thiomorpholinyl, thiomorpholinyl sulfoxide and thiomorpholinyl sulfone Includes, but is not limited to. Heterocyclyl groups are substituted by R ⁶ as defined in the Summary of the Invention, or as defined herein, hydroxy, mercapto, halo, alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, phenylalkenyl, alkoxy , Phenoxy, phenylalkoxy, haloalkyl, haloalkoxy, formyl, nitro, cyano, amidino, cycloalkyl, hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, ureido, alkoxycarbonylamino, Amino, monoalkylamino, dialkylamino, monophenylamino, monophenylalkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monophenylaminoalkyl, monophenylalkylaminoalkyl, alkylcarbonyl, carboxyalkyl, Alkoxycarbonylalkyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl and It may be optionally substituted by one or more substituents selected from the group consisting of imidazolyl.

"Heterocyclylalkyl" means a group of the formula -R _a -R _e wherein R _a is an alkyl group as defined above and R _e is a heterocyclyl group as defined above, and examples thereof include 2- (1, 3-benzodioxol-5-yl) ethyl and 3- (1,4-benzodioxan-6-yl) propyl and the like.

"Monoalkylamino" means a group of the formula -N (H) R _a , wherein R _a is an alkyl group as defined above, and examples thereof include methylamino, ethylamino and propylamino and the like.

"Monoalkylaminocarbonyl" means a group of the formula -C (O) N (H) R _a , wherein R _a is an alkyl group as defined above, examples include methylaminocarbonyl, ethylaminocarbonyl and Propylaminocarbonyl and the like.

"Monoalkylaminosulfonyl" means a group of the formula -S (O) ₂ N (H) R _a , wherein R _a is an alkyl group as defined above, for example methylaminosulfonyl, ethylaminosulfonyl And propylaminosulfonyl and the like.

"N-heterocyclyl" means the heterocyclyl group containing at least one nitrogen atom and attached to the main structure via the nitrogen atom. N-heterocyclyl groups may further contain up to three heteroatoms. Examples include piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, azetidinyl, indolyl, pyrrolyl, amidazolyl, tetrahydroisoquinolyl, perhydroazinyl, Tetrazolyl, triazolyl, oxazinyl and the like, which may also be optionally substituted as described for the heterocyclyl group above. In addition to being optionally substituted by the substituents described above for the heterocyclyl group, the N-heterocyclyl group may be optionally substituted by R ⁶ described in the Summary of the Invention.

"Phenylalkyl" means the alkyl group substituted by a phenyl group, for example benzyl and the like.

"Any" or "optionally" means that the situation described below may or may not occur, and this description includes cases where and when such an event or situation has occurred. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and this description includes both substituted and unsubstituted aryl groups. The term "-[C ₂ -C ₈ alkyl] -R ¹⁰ (which may be optionally substituted by hydroxy)" means that the alkyl has any substituents. The same is true for the term “-[C ₁ -C ₈ alkyl] -R ¹¹ (which may be optionally substituted by hydroxy)”. The term "-S (O) _t R ²² which may be optionally substituted" means that all R ²² substituents have any substituents.

"Phenylalkenyl" means the alkenyl group substituted by a phenyl group.

The term "pharmaceutically acceptable salts" means salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids, inorganic bases, organic acids and organic bases. When the compounds of the present invention are basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Pharmaceutically acceptable acid addition salts of the compounds of the present invention include acetates, benzenesulfonates (besylates), benzoates, camphorsulfonates, citrates, ethenesulfonates, fumarates, gluconates, glutamate, hydrogen bromide Acid salts, hydrochlorides, isethionates, lactates, maleates, malates, mandelates, methanesulfonates, muxates, nitrates, pamolates, pantothenates, phosphates, succinates, sulfates, tartarates and p-toluenesulfonates Etc. are included. Where the compound contains an acidic side chain, pharmaceutically acceptable suitable base addition acids of the compounds of the invention include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or lysine, N, N'-dibenzyl Organic salts made from ethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

A "therapeutically effective amount" means an amount of a compound of the present invention sufficient to treat an abnormality in nitric oxide production when administered to a human having an abnormality in nitric oxide production. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" depends on the compound, the symptoms and the severity thereof, and the age of the human being treated, but a person of ordinary skill in the art would appreciate their knowledge and the disclosure herein. The amount will usually be determined based on this.

As used herein, “treating” or “treatment” collectively refers to treating a human condition resulting from abnormalities in nitric oxide production,

(i) preventing the occurrence of such symptoms, particularly in humans susceptible to such symptoms but not yet diagnosed as having,

(ii) inhibiting the symptoms, ie inhibiting the occurrence of the symptoms, or

(iii) alleviating the symptoms, ie regressing the symptoms.

The yield of each reaction described herein is expressed as a percentage of theoretical yield.

Since most compounds described herein contain one or more asymmetric centers, they can be defined as (R)-or (S)-in terms of pure stereochemistry or as (D)-or (L)-for amino acids. Possible enantiomers, diastereomers and other stereoisomeric forms can occur. The present invention includes not only all of the possible isomers, but also both racemic and optically pure forms. Optically active (R)-and (S)-, or (D)-and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Can be. When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise defined, the compounds include both E and Z geometric isomers. Similarly, tautomers are included in the present invention.

The nomenclature used herein is described in I.U.P.A.C. As a modification of the nomenclature system, the compounds of the present invention are referred to herein as amide derivatives. For example, a compound of the present invention having the formula: 2 [[3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl ) -6-methylpyrimidin-4-yl] amino] -N, N-diethylacetamide is named:

Unless stated otherwise, names of compounds include all single stereoisomers, enantiomers, racemates or mixtures thereof.

Utility of the Compounds of the Invention

Nitric oxide produced by inducible forms of nitric oxide synthase (i-NOS) is known to be involved in the development of a number of inflammatory and autoimmune diseases and is not generally considered an inflammatory disease but nevertheless It may be associated with cytokines that locally upregulate i-NOS. The compounds of the present invention, either alone or in combination with other pharmaceutical adjuvants, are useful for treating mammals, preferably humans, who develop symptoms from abnormalities in nitric oxide production. Such symptoms include multiple sclerosis (Parkinson, J. F. et al., J. Mol. Med. (1997), Vol. 75, pp. 174-186); Stroke or cerebral ischemia (ladecola, C. et al., J. Neurosci. (1997), Vol. 17, pp. 9157-9164); Alzheimer's Disease (Smith, MA et al., J. Neurosci. (1997), Vol. 17, pp. 2653-2657; Wallace, MN et al., Exp. Neurol. (1997), Vol. 144, pp. 266 -272); HIV dementia (Adamson D. C. et al., Science (1996), Vol. 274, pp. 1917-1921); Parkinson's disease (Hunot, S. et al., Neuroscience (1996), Vol. 72, pp. 355-363); Meningitis (Koedel, U. et al., Ann. Neurol. (1995), Vol. 37, pp. 313-323); Expanded cardiomyopathy and congestive heart failure (Satoh M et al., J. Am. Coll. Cardiol. (1997), Vol. 29, pp. 716-724); Atherosclerosis (Wilcox, J. N. et al., Arterioscler. Thromb. Vasc. Biol. (1997), Vol. 17, pp. 2479-2488); Restenosis or transplantation stenosis, septic shock and hypertension (Petros, A. et al., Cardiovasc. Res. (1994), Vol. 28, pp. 34-39); Hemorrhagic shock (Thiemermann, C. et al., Proc. Natl. Acad. Sci. (1993), Vol. 90, pp. 267-271); Asthma (Barnes, PJ, Ann. Med. (1995), Vol. 27, pp. 389-393; Flak, TA et al., Am. J. Respir. Crit.Care Med. (1996), Vol. 154, pp. S202-S206); Adult respiratory distress syndrome, smoking or particulate mediated lung injury (Ischiropoulos, H. et al., Am. J. Respir. Crit. Care Med. (1994), Vol. 150, pp. 337-341; Van Dyke, K., Agents Actions (1994), Vol. 41, pp. 44-49); Pathogen-mediated pneumonia (Adler, H. et al., J. Exp. Med. (1997), Vol. 185, pp. 1533-1540); Trauma of various etiologies (Thomae, K. R. et al., Surgery (1996), Vol. 119, pp. 61-66); Rheumatoid arthritis and osteoarthritis (Grabowski, P. S. et al., Br. J. Rheumatol. (1997), Vol. 36, pp. 651-655); Glomerulonephritis (Weinberg, J. B. et al., J. Exp. Med. (1994), Vol. 179, pp. 651-660); Systemic lupus erythematosus (Belmont, H. M. et al., Arthritis Rheum. (1997), Vol. 40, pp. 1810-1816); Inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (Godkin, AJ et al., Eur. J. Clin. Invest. (1996), Vol. 26, pp. 867-872; Singer, II et al., Gastroenterology (1996 ), Vol. 111, pp. 871-885); Insulin dependent diabetes mellitus (McDaniel, M. L., et al., Proc. Soc. Exp. Biol. Med. (1996), Vol. 211, pp. 24-32); Diabetic neuropathy or nephropathy (Sugimoto, K. and Yagihashi, S., Microvasc. Res. (1997), Vol. 53, pp. 105-112; Amore, A. et al., Kidney Int. (1997) , Vol. 51, pp. 27-35); Acute and chronic organ transplant rejection (Worrall, N. K. et al., Transplantation (1997), Vol. 63, pp. 1095-1101); Graft angiopathy (Russell, M. E. et al., (1995), Vol. 92, pp. 457-464); Graft-versus-host disease (Kichian, K. et al., J. Immunol. (1996), Vol. 157, pp. 2851-2856); Psoriasis and other inflammatory skin diseases (Bruch-Gerharz, D. et al., J. Exp. Med. (1996), Vol. 184, pp. 2007-2012); And cancer (Thomsen, L. L. et al., Cancer Res. (1997), Vol. 57, pp. 3300-3304).

In addition, the compounds of the present invention may be useful for managing male and female reproductive function, alone or in combination with other drugs commonly used for male and female reproductive function management. Examples include fertility suppression, intrauterine reception and implantation (alone or in combination with progesterone antagonists), contraception contraception (alone or in combination with progesterone antagonists), induction of abortion (in combination with antiprogestins, and further in combination with prostaglandins Control and management of pain and delivery, treatment of cervical insufficiency (alone or in combination with progesterone or progestin), and treatment of endometriosis (alone or with LHRH-agonist / antagonist, antiprogestin or progestin) In combination with sequential or simultaneous administration with other drugs), but is not limited thereto. In this regard, Chwalisz, K. et al., J. Soc. Gynecol. Invest. (1997), Vol. 4, No. 1 (Supplement), page 104a], in combination with antiprogestin and further in combination with prostaglandins to discuss abortion induction and discuss control and management of analgesia and delivery [Chwalisz, K. et al., Prenat. Neonat. Med. (1996), Vol. 1, pp. 292-329], and alone or in combination with progesterone or progestin, Chwalisz, K. et al., Hum. Reprod. (1997), vol. 12, pp. 101-109.

Those skilled in the art will appreciate that 1-substituted imidazoles will be included in the present invention. Compounds of this class have been previously known as cytochrome P450 enzymes (Maurice, M. et al., FASEB J. (1992), Vol. 6, pp. 752-8) and nitric oxide synthesis (Chabin, R. NM. Et al. , Biochemistry (1996), Vol. 35, pp. 9567-9575), has been described as a heme-binding inhibitor. Accordingly, the compounds of the present invention are useful in steroid and retinoid biosynthesis (Masamura et al., Breast Cancer Res. Treat. (1995), Vol. 33, pp. 19-26; Swart, P. et al., J. Clin. Endocrinol. Metab., Vol. 77, pp. 98-102; Docks, P. et al., Br. J. Dermatol. (1995), Vol. 133, pp. 426-32) and cholesterol biosynthesis (Burton, PM et al., Biochem. Pharmacol. (1995), Vol. 50, pp. 529-544; Swinney, DC et al., Biochemistry (1994), Vol. 33, pp. 4702-4713). It may be useful as an inhibitor of cytochrome P450 family members selected for therapeutic purposes, including but not limited to. In addition, the imidazole compound may have antifungal activity (Aoyama, Y. et al., Biochem. Pharmacol. (1992), Vol. 44, pp. 1701-1705). P450 inhibitory activity of the compounds of the invention can be assessed using a suitable assay system specific for the desired isoform of P450. Such assays are included in the references cited above. One additional example of a mammalian cytochrome P450 isotype that can be inhibited by a compound of the present invention is cytochrome P450 3A4, which is described in Yamazaki et al., Carcinogenesis (1995), Vol. 16, pp. 2167-2170 can be evaluated similarly to the method described.

Test of Compounds of the Invention

Nitric oxide synthase is a complex enzyme that catalyzes the reaction of converting L-arginine to nitric oxide (NO) and citrulline. Catalysis proceeds by two consecutive oxidations of the guanidinium group of L-arginine.

Compounds of the present invention were evaluated using a cell-based nitric oxide synthase assay, which measures nitrite, the oxidation product of nitric oxide, in conditioned media of cultured cells. Rat monocyte cell lines RAW 264.7 and J774 are well known cell lines that are capable of producing more than 10 μM of nitrite in response to immunostimulation.

INOS Induction in RAW 264.7 Mouse Monocytes

Rat RAW 264.7 macrophages were obtained from American Type Culture Collection (Rockville, Maryland), RPMI 1640 (conserved containing 10% calf fetal serum (FBS), 5000 units / ml penicillin and streptomycin, and 2 mM glutamine). Medium). NOS activity was determined by fluorescence analysis of nitrite, an oxidation product of nitric oxide (Diamani et al., Talanta (1986), Vol. 33, pp. 649-652). Induction of iNOS (inducible nitric oxide synthase) is stimulated by treating cells with lipopolysaccharide and γ-interferon. The method is described below.

Cells are harvested and diluted to 500,000 cells / ml using preservation medium and seeded at 100 μl / well in 96-well plates. The plates are incubated in a 37% 5% CO ₂ atmosphere. Here, medium in 90 μl of BME medium containing 10% FBS, 100 units / ml penicillin, 100 μl streptomycin, 2 mM glutamine, 100 units / ml interferon-γ and 2 μg / ml lipopolysaccharide Replace. Using 10 μl of 2 mM stock solution in 100 mM Hepes (pH 7.3) + 0.1% DMSO, N-guanidino-methyl-L-arginine was added to 4 wells (negative control) at a final concentration of 200 μM and 4 Wells (positive control) are fed only 100 mM Hepes / 0.1% DMSO buffer. Compounds for evaluation are dissolved at 10 times the desired concentration in Hepes / DMSO and 10 μl of this solution is transferred to 96-well plates. The plate is incubated for 17 hours under 37% 5% CO ₂ atmosphere. Nitrite accumulated in the medium is measured as follows: 15 μl of 2,3-diaminonaphthalene (10 μg / ml in 0.75 M HCl) is added to each well and incubated for 10 minutes at room temperature. 15 μl of 1 N NaOH is added and fluorescence emission is measured at 405 nm using an excitation wavelength of 365 nm. The values of the positive and negative controls are used to normalize the enzyme activity of the experimental wells as a percentage of the control. The signal-to-noise ratio for the analysis exceeded 10.

When tested by this assay, it has been demonstrated that the compounds of the present invention can inhibit nitric oxide production.

Various in vitro assays can be used to determine the efficacy of the compounds of the invention in treating symptoms arising from abnormalities in nitric oxide production, such as arthritis. The description below relates to such assays using mice.

Effect of Compounds of the Invention on Adjuvant-Induced Arthritis in Rats

Skin of male Lewis rats was injected with 0.1 ml of Mycobacterium butyricum (10 μg / ml) in incomplete Freund's adjuvant. The day after the immunization with the adjuvant, the experiment was started by subcutaneous (bid) administration of the vehicle (acidified saline, 1 ml / kg) or the compound of the present invention (3, 10 or 30 ml / kg) and continued until the end of the experiment. (Population of treated rats = 10). Clinical scores (see below) were measured in all limbs three times weekly throughout the study period. Mice were euthanized 34 to 35 days after immunization. Radiation evaluation of the hind paw when euthanizing (see below) was performed, blood samples were collected for clinical blood chemistry and the amount of drug (6-12 hours after the last dose only for high dose groups), and the potential toxicity measured. Cross sections of the hepatic liver were obtained and the posterior limbs were stored for histopathological measurements.

Clinical Score-The grade of each limb was determined according to the following steps.   0 No inflammatory signal   One Moderate redness, primary signs of swelling, easy bending of joints   2 Moderate redness, moderate swelling, easy bending of joints   3 Redness, significant swelling, distorted feet, joints begin to fuse   4 Redness, swelling, distorted feet, joints fully fused

Radiation scores were graded in steps of 0 to 3 for the parameters of swelling of soft tissue, loss of cartilage, erosion and ectopic ossification, with each posterior limb.

When tested by this assay, the compounds of the present invention have been shown to be able to treat arthritis in mice.

Those skilled in the art will appreciate that there are a number of assays for the activity of NOS isotypes (iNOS, nNOS and eNOS) that can be used to assess the biological activity of the compounds of the present invention. Such assays include assays for native NOS isotypes in tissues studied ex vivo (Mitchell et al., Br. J. Pharmacol. (1991), Vol. 104, pp. 289 291; Szabo et al., Br. J. Pharmacol. (1993), Vol. 108, pp. 786-792; Joly et al., Br. J. Pharmacol. (1995), Vol. 115, pp. 491-497), as well as primary cell cultures. And assays for cell lines (Forstermann et al., Eur. J. Pharmacol. (1992), Vol. 225, pp. 161-165; Radmoski et al., Cardiovasc. Res. (1993), Vol. 27, pp. Wang et al., J. Pharmacol. Exp. Ther. (1994), Vol. 268, pp. 552-557). Those skilled in the art will appreciate that recombinant NOS enzymes may be transiently transfected in heterologous cells (Karlsen et al., Diabetes, (1995), Vol. 44, pp. 753-758) or stable transfection (McMillan et al., Proc. Natl. Acad. (1992), Vol. 89, pp. 11141-11145; Sessa et al., J. Biol. Chem. (1995), Vol. 270, pp. 17641-17644), or lytic virus transfection NOS cDNA via Busconi & Michel, Mol. Pharmacol. (1995), Vol. 47, pp. 655-659; List et al., Biochem. J. (1996), Vol. 315, pp. 57-63). It will be appreciated that can be expressed using. Heterologous expression is observed in mammalian cells (McMillan et al., Proc. Natl. Acad. Sci. (1992), Vol. 89, pp. 11141-11145), insect cells (Busconi & Michel, Mol. Pharmacol. (1995), Vol. 47, pp. 655-659; List et al., Biochem. J. (1996), Vol. 315, pp. 57-63), Yeast (Sari et al., Biochemistry (1996), Vol. 35, pp. 7204-7213) or bacteria (Roman et al., Proc. Natl. Acad. Sci. (1995), Vol. 92, pp. 8428-8432; Martasek et al., Biochem. Biophys. Res. Commun. ( 1996), Vol. 219, pp. 359-365). Any of these heterologous expression systems can be used to establish iNOS, nNOS and eNOS assay systems to assess the biological activity of the compounds of the present invention.

Administration of Compounds of the Invention

Any suitable route of administration may be used to provide an effective dosage of a compound of the invention to a patient. For example, oral administration, rectal administration, parenteral (subcutaneous, intramuscular, intravenous) administration, transdermal administration, and similar dosage forms can be used. Dosage forms include tablets, pills, dispersions, suspensions, solutions, capsules and patches.

Pharmaceutical compositions of the invention comprise a compound of the invention as an active ingredient, and may also contain a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. Carriers such as starch, sugar and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants are suitable for oral solid preparations (powders, capsules and tablets), and oral solid preparations are oral More preferred than liquid formulations. Their method of preparation is well known in the art.

Because of their ease of administration, tablets and capsules are the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are used. If desired, tablets may be coated by standard water soluble or water soluble techniques. In addition to the conventional dosage forms described above, the compounds of the present invention may be administered by controlled release means or sustained release means and delivery devices.

Pharmaceutical compositions of the invention suitable for oral administration may be presented in discrete units such as capsules, cachets or tablets, each of which may be a powder or granule, or a solution or suspension in an aqueous solution, non-aqueous solution, oil-in-water emulsion or water-in-oil emulsion. It contains a predetermined amount of active ingredient as a agent. Such compositions may be prepared by any method in pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more essential ingredients. Typically, the composition is homogeneously and intimately mixed with the active ingredient with a liquid carrier or finely divided solid carrier or both, and then the product is shaped into the desired formulation as needed.

Preferred Embodiment

Among the compounds of formula (Ya), formula (Yb) and formula (Yc) of the invention described in the above summary of the invention, the preferred group of compounds is n is 1, m is 2 or 3 and A is -C (O) OR ¹ or -C (O) N (R ¹ ) R ² , W is CH, R ¹ is hydrogen or alkyl, R ² is hydrogen, alkyl,-(CH ₂ ) _n -N (R ¹ ) ₂ , compounds of formula (Yc) which are optionally substituted heterocyclylalkyl or optionally substituted aralkyl.

Among the small groups of compounds, a preferred class of compounds wherein R ⁴ is -N (R ¹ ) R ² , wherein R ¹ is hydrogen, R ² is (1,3-benzodioxol-5-yl) methyl and (1 , 4-benzodioxan-6-yl) methyl; and heterocyclylalkyl selected from the group consisting of.

Among these compounds, preferred compounds are

2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] acetic acid, ethyl ester;

2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] -N, N-diethylacetamide;

2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] -N- (2-dimethylaminoethyl) acetamide;

2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] acetamide;

2-[[3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N, N-diethylacetamide;

2-[[3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N-methylacetamide;

2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N-methylacetamide;

2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N, N-diethylacetamide;

2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino Acetamide; And

2-[[(3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] Amino] acetamide.

Among the preferred small group of compounds, the preferred class of compounds are those wherein R ⁴ is heterocyclyl.

Among these classes of compounds, preferred compounds are

2-[[pyridin-3-ylmethyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodi Oxol-5-yl) ethyl] acetamide;

2-[[2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] [(1,3-benzodioxol-5-yl) methyl] amino] -N- [ 2- (1,3-benzodioxol-5-yl) ethyl] acetamide; And

2-[[2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] [2- (morpholin-4-yl) ethyl] amino] -N- [2- (1 , 3-benzodioxol-5-yl) ethyl] acetamide.

Among these small groups of compounds, another preferred class of compounds is that R ⁴ is hydroxy, cyano, -N (R ¹ ) R ² , -N (R ¹ ) -C (O) -R ¹ , -N (R ¹ ) -C (O) OR ¹ , -N (R ¹ ) -S (O) _t -R ¹ or -N (R ¹ ) -C (O) -N (R ¹ ) ₂ , wherein R ¹ and R ² are each independently hydrogen, alkyl or aralkyl.

Among these classes of compounds, preferred compounds are

2-[[3-hydroxypropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol -5-yl) ethyl] acetamide;

2-[[2-cyanoethyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol -5-yl) ethyl] acetamide;

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzo Dioxol-5-yl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzo Dioxol-5-yl) ethyl] acetamide;

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3 -Benzodioxol-5-yl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, 3-benzodioxol-5-yl) ethyl] acetamide;

2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3- Benzodioxol-5-yl) ethyl] acetamide;

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol- 5-yl) ethyl] acetamide;

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl) ethyl] Acetamide;

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-meth Methoxyphenyl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4- Methoxyphenyl) ethyl] acetamide;

2-[[(3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-meth Methoxyphenyl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide;

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzodioxane- 6-yl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, 4-benzodioxane-6-yl) ethyl] acetamide;

2-[[3- (di (phenylmethyl) amino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1 , 4-benzodioxane-6-yl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide;

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4 -Benzodioxane-6-yl) ethyl] acetamide;

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide;

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide;

2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide;

2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4- Benzodioxan-6-yl) ethyl] acetamide;

2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3- Dihydrobenzofuran-5-yl) ethyl] acetamide;

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-dihydrobenzofuran -5-yl) ethyl] acetamide;

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3- Dihydrobenzofuran-5-yl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl] acetamide;

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3 -Dihydrobenzofuran-5-yl) ethyl] acetamide;

2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide; And

2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide.

Preparation of Compounds of the Invention

Schemes 1-4 illustrate methods for preparing compounds of formula (Yc). Compounds of formula (Ya) and formula (Yc) can be prepared analogously.                 

Compounds of formula (Y ₁ ), (Y ₂ ), (Y ₄ ) and (Y ₅ ) are either commercially available or prepared by methods disclosed herein or by methods well known to those of ordinary skill in the art. can do. R ¹ , R ² , m and n are each independently as described in the Summary of the Invention for the compounds of Formula (Ya), Formula (Yb) and Formula (Yc); R ⁵ and W are also as described in the above summary of the compounds of the formulas (Ya), (Yb) and (Yc).

The synthesis may also be carried out as follows:

4-chloro-6-methyl-2-methylsulfonylpyrimidine (N-cyanoethylglycine, ethyl ester (15.9 g, 102 mmol) (compound of formula (Y ₂ )) dissolved in DMSO (70 mL) ( 18.8 g, 91 mmol) (compound of formula (Y ₁ )) and diisopropylethylamine (18 mL, 100 mmol) were added. After stirring for 16 hours, the reaction temperature was raised to 70 ° C. and imidazole (26.5 g, 0.39 mmol) was added. After stirring for 1 day, the reaction was cooled to room temperature and placed in cold water. The resulting solid was suction filtered and collected on paper to yield 9.9 g of 2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] Acetic acid and ethyl ester (compound of formula (Yc1)) were obtained.

2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] acetic acid, ethyl ester (4.51) dissolved in THF (250 mL) g, 14.4 mmol) was added LiOH (0.91 g, 21.7 mmol) and water (30 mL). After stirring for 18 hours, most solvents were removed in vacuo and 1 N HCl (21.7 mL, 21.7 mmol) was added. The resulting solid was filtered off with suction and collected on paper to give 3.17 g of 2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] Acetic acid (compound of formula (Yc2)) was obtained.

2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] acetic acid (1.53 g) slurried in DMF (25 mL) , 5.3 mmol) was added to carbonyldiimidazole (0.87 g, 5.4 mmol). After stirring for 2 hours, diethylamine (1.0 mL, 9.7 mmol) (compound of formula (Y ₄ )) was added. After stirring for 18 hours, the reaction was partitioned between ethyl acetate and water. The organic layer was separated and dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 0.91 g of 2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyridine Midin-4-yl] amino] -N, N-diethylacetamide (compound of formula (Yc3)) was obtained.

The compound of formula (Yc3) and its derivatives are 2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl as an appropriately substituted starting material ] Amino] -N-methylacetamide and 2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [ Prepared in a similar manner using 2- (1,4-benzodioxan-6-yl) ethyl] acetamide.

2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N, N-di dissolved in MeOH (25 mL) Ammonia (g) was bubbled with ethylacetamide (0.22 g, 0.65 mmol). Raney Nickel (0.8 g) was added and the mixture was placed under 50 psi of nitrogen. When the reaction was found to be complete by TLC, the reaction mixture was suction filtered through Celite and the solvent was removed in vacuo. To the residue dissolved in MeOH (10 mL) was added piperonal (0.29 g, 1.9 mmol) and NaBH (OAc) ₃ (0.40 g, 1.9 mmol). After 18 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and bicarbonate aqueous solution. The organic layer was separated and dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. Chromatography on silica with acetonitrile / ammonium hydroxide (19/1) gives 2-[[3- (1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazole -1-yl) -6-methylpyrimidin-4-yl] amino] -N, N-diethylacetamide (compound of formula (Yc4)) was obtained;

A compound of the formula (Yc4) and a derivative thereof is 2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazole) as an appropriately substituted starting material. -1-yl) -6-methylpyrimidin-4-yl] amino] -N-methylacetamide;

2-[[3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N-methylacetamide;

2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N, N-diethylacetamide;

2-[[3- (1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] Acetamide;                 

및

And

2-[[3- (1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] Acetamide;

Prepared in a similar manner.

Compounds of formula (Y ₄ ) wherein R ² is 2- (1,4-benzodioxan-6-yl) ethyl can be prepared as follows, and reacted with a compound of formula (Yc2) to Compounds may be prepared and further reacted as above to produce compounds of formula (Yc4).

To 1,4-benzodioxane-6-carboxaldehyde (10.0 g, 60 mmol) in acetic acid (50 mL) was added nitromethane (6.3 mL, 1.9 eq.) And ammonium acetate (5.1 g, 1.1 eq.) It was. After heating at 110 ° C. for 4 hours, the mixture was cooled to room temperature, water (150 mL) was added and the solid precipitate collected by filtration. This solid was crystallized from methylene chloride-hexane (1: 1, 45 mL) to give 7.6 g (61%) of 6- (2-nitroethenyl) -1,4-benzodioxane. To a portion of the solid (3.58 g) dissolved in MeOH-EtOH-AcOEt (1: 1: 1, 450 mL) was added 10% Pd / C (1.7 g) and concentrated HCl (3.3 mL, 2.3 eq). After shaking for 5 hours at 45 psi in a Parr hydrogenation reactor, the catalyst was removed by filtration through celite and washed with methanol. The filtrate was evaporated to afford 3.59 g (96%) of 1,4-benzodioxane-6-ethanamine, hydrochloride.

Alternatively, the compound of formula (Y ₃ ) is reacted as follows to produce a compound of formula (Yc3) wherein both R ¹ and R ² are hydrogen, which is further reacted with a compound of formula (Y5) ) Can be prepared.

2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl slurried in MeOH (50 mL) and cooled in a dry ice / acetone bath ] Amino] acetic acid, ethyl ester (2.3 g, 7.3 mmol) was bubbled NH ₃ . The bomb was sealed and heated in an oil bath at 65 ° C. for 2 days. The reaction was cooled and opened in a dry ice / acetone bath. The solid was filtered off with suction to obtain 1.7 g of 2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] acetamide.

Scheme 2 illustrates another method for preparing a compound of formula (Yc). Compounds of formula (Ya) and formula (Yb) can be prepared analogously.                 

Compounds of formula (Y ₁ ), (Y ₆ ), (Y ₇ ), (Y ₉ ) and (Y ₅ ) are commercially available or are well known to those of ordinary skill in the art or methods disclosed herein. It can be manufactured by a known method. R ¹ , R ² , m and n are each independently as described in the Summary of the Invention for the compounds of Formula (Ya), Formula (Yb) and Formula (Yc); R ⁴ , R ⁵ and W are also as described in the above summary of the compounds of the formulas (Ya), (Yb) and (Yc).

The synthesis may also be carried out as follows:

Homopiperonylamine hydrochloride (2.14 g, 10.6 mmol) (compound of formula (Y ₇ )) in CH ₂ Cl ₂ (20 mL) in an ice bath in triethylamine (3.1 mL, 21 mmol) and chloroacetyl chloride (0.85 mL, 10 mmol) (compound of formula (Y ₆ )) was added. After warming to room temperature and stirring for 16 hours, the reaction was partitioned with 1 N HCl. The organic layer was separated, washed with an aqueous bicarbonate solution and dried (Na ₂ SO ₄ ), and then the solvent was removed in vacuo to give 1.8 g of 2-chloro-N- [2- (1,3-benzodioxol-5-yl ) Ethyl] acetamide (compound of formula (Y ₈ )) was obtained.

3-aminopropanol (0.72 mL, 9.4 mmol) in 2-chloro-N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide (0.45 g, 1.9 mmol) in ethanol (10 mL) ) (Compound of formula (Y ₉ )) was added. The reaction was heated to 60 ° C. in an oil bath for 1 day and then the reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried (Na ₂ SO ₄ ), then the solvent was removed in vacuo to remove 0.44 g of 2-[(3-hydroxypropyl) amino] -N- [2- (1,3- Benzodioxol-5-yl) ethyl] acetamide (compound of formula (Y ₁₀ )) was obtained.

2-[(3-pyridinylmethyl) amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide, which is a suitably substituted starting material of the following formula (Y ₁₀ ) , 2-[[2- (4-morpholinyl) ethyl] amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide and 2-[(1,3- Prepared in a similar manner from benzodioxol-5-ylmethyl) amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide.

4-chloro in 2-[(3-hydroxypropyl) amino] -N- (1,3-benzodioxol-5-ylmethyl) acetamide (0.44 g, 1.6 mmol) dissolved in DMSO (5 mL). -6-methyl-2-methylsulfonylpyrimidine (0.31 g, 1.5 mmol) (compound of formula (Y ₁ )) and diisopropylethylamine (0.55 mL, 3.1 mmol) were added. After stirring for 16 hours, the reaction temperature was raised to 70 ° C. and imidazole (0.47 g, 6.9 mol) was added. After stirring for 1 day, the reaction was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. Chromatography on silica with CH ₂ Cl ₂ / MeOH gives 2-[[3-hydroxypropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide (compound of formula (Yc5)) was obtained.

A compound of the formula (Yc5) and a derivative thereof are suitably substituted starting materials

2-[[pyridin-3-ylmethyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodi Oxol-5-yl) ethyl] acetamide;

2-[[2-cyanoethyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol -5-yl) ethyl] acetamide;

2-[[3- (1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine-4- General] amino] acetic acid, ethyl ester;

2-[[2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] [2- (morpholin-4-yl) ethyl] amino] -N- [2- (1 , 3-benzodioxol-5-yl) ethyl] acetamide;

및

And

2-[[2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] [(1,3-benzodioxol-5-yl) methyl] amino] -N- [2 -(1,3-benzodioxol-5-yl) ethyl] acetamide;

Prepared in a similar manner.

Alternatively, the compound of formula (Y ₁₀ ) and its derivatives were prepared as follows:

In a manner similar to the preparation of formula (Yc3) above, 2-[(2-cyanoethyl) (dimethylethoxycarbonyl) amino] acetic acid (8.3 g, 39 mmol) dissolved in CH ₂ Cl ₂ (100 mL) To carbonyldiimidazole (6.2 g, 38 mmol) was added. After stirring for 30 minutes, homopiperonylamine, hydrochloride (8.0 g, 41 mmol) and diisopropylethylamine (7.5 mL, 43 mmol) were added. After stirring for 18 hours, most solvent was removed in vacuo and the residue partitioned between ethyl acetate and 1 N HCl. The organic layer was separated, washed with aqueous bicarbonate solution and brine, dried (Na ₂ SO ₄ ), and then the solvent was removed in vacuo to give 13 g of 2-[(2-cyanoethyl) (dimethylethoxycarbonyl) amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide was obtained.

2-[(2-cyanoethyl) (dimethylethoxycarbonyl) amino] -N- [2- (1,3-benzodioxol-5- in CH ₂ Cl ₂ (75 mL) cooled in an ice bath. To the ethyl) acetamide (14 g, 37 mmol) was added trifluoroacetic acid (50 mL). After stirring for 1 hour, the ice bath was removed and the solvent was removed in vacuo. The residue was triturated with ether to give a solid. The solid was collected by filtration to give 12 g of 2-[(2-cyanoethyl) amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide, trifluoro Acetic acid salt (compound of formula (Y ₁₀ )) was obtained.

Alternatively, the compound of formula (Y ₁₀ ) and its derivatives were prepared as follows:

Piperonyl chloride (50 g, mmol) was added to N-methyl-β-alaninenitrile (50 g, mmol) in acetonitrile. After stirring for 18 hours, the solvent was removed in vacuo. The residue was dissolved in CH ₂ Cl ₂ , washed with aqueous carbonate solution, then dried (MgSO ₄ ) and the solvent removed in vacuo. The residue was dissolved in methanol (600 mL) saturated with ammonia and Raney nickel (10 g) was added. After shaking for 6 hours under a nitrogen atmosphere of 20 psi, the reaction was filtered through celite and the solvent was removed in vacuo to give 65 g of N- (1,3-benzodioxol-5-ylmethyl) -N- Methyl-1,3-propanediamine was obtained.

Ethyl glyoxalate (50 in N- (1,3-benzodioxol-5-ylmethyl) -N-methyl-1,3-propanediamine (33 g, 0.15 mol) in CH ₂ Cl ₂ (500 mL) 30 ml of% toluene solution, 0.15 mol) and sodium triacetoxyborohydride (40 g, 0.19 mol) were added. After stirring for 4 hours, the reaction was washed with aqueous potassium carbonate solution and the solvent removed in vacuo. Chromatography on silica with CH ₂ Cl ₂ / MeOH / ammonium hydroxide gave 14 g of 2-[[3-[(1,3-benzodioxol-5-ylmethyl) amino] propyl] amino] acetic acid, ethyl Ester (compound of formula (Y ₁₀ )) was obtained.

Scheme 3 illustrates another method for preparing a compound of formula (Yc). Compounds of formula (Ya) and formula (Yb) can be similarly prepared using suitably substituted starting materials.                 

Compounds of formula (Yc3) were prepared by the methods disclosed herein. R ¹ , R ² , m and n are each independently as described in the Summary of the Invention for the compounds of Formula (Ya), Formula (Yb) and Formula (Yc); R ⁵ and W are also as described in the above summary of the compounds of the formulas (Ya), (Yb) and (Yc).

The synthesis may also be carried out as follows:

2-[(2-cyanoethyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1 in MeOH (50 mL) Ammonia was bubbled into, 3-benzodioxol-5-yl) ethyl] acetamide (2.5 g, 5.8 mmol) (compound of formula (Yc3)). Raney nickel (1.0 g of 50% slurry) was added and placed at 50 psi in the Parr hydrogenation reactor. After shaking for 16 hours, the pressure was released and the reaction mixture was suction filtered through celite. The solvent is removed in vacuo and the residue is chromatographed on silica (9: 1 CH ₃ CN / NH ₄ 0H) to give the compound of formula (Yc6) 2-[[3-aminopropyl] [2- (1H -Imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide as a white solid;

A compound of the formula (Yc5) and a derivative thereof are suitably substituted starting materials

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl) ethyl] Acetamide;

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzodioxane- 6-yl) ethyl] acetamide;

및

And

2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-dihydrobenzofuran -5-yl) ethyl] acetamide;

Prepared in a similar manner.

Compounds of formula (Yc6) can be used to prepare compounds of formulas (Yc7), (Yc8) and (Yc9) as follows:

2-[(3-aminopropyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (dissolved in MeOH (10 mL) To 1,3-benzodioxol-5-yl) ethyl] acetamide (0.3 g, 0.7 mmol) (compound of formula (Yc6)) formalin (0.15 mL, 2.0 mmol) and sodium triacetoxyborohydride (0.37 g, 1.7 mmol) was added. After stirring for 16 hours, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and bicarbonate aqueous solution. The organic layer was separated, washed with brine and dried (Na ₂ SO ₄ ), then the solvent was removed in vacuo. Chromatography on silica with acetonitrile / ammonium hydroxide to yield 0.14 g of 2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine-4- Il] amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide (compound of formula (Yc8)) was obtained;

2-[(3-aminopropyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, in methanol) (2 mL) To benzaldehyde (0.2 M in methanol, 68 μl, 0.14 mmol) was added to 3-benzodioxol-5-yl) ethyl] acetamide (50 mg, 0.11 mmol) (compound of formula (Yc6)). After stirring for 15 hours, borane-pyrimidine complex (0.2 M in methanol, 0.14 mmol) was added. After 2 hours, the solution was evaporated. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica (2: 1 ethyl acetate / hexane) to give 2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methyl Pyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide (compound of formula (Yc8)) was obtained as a white solid;

Compounds of formula (Yc8) and derivatives thereof are suitably substituted starting materials

2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxy Phenyl) ethyl] acetamide;

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide;

2-[[3- (di (phenylmethyl) amino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1 , 4-benzodioxane-6-yl) ethyl] acetamide;

2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4- Benzodioxan-6-yl) ethyl] acetamide;

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide;

2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3- Dihydrobenzofuran-5-yl) ethyl] acetamide;

및

And

2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide;

Prepared in a similar manner.                 

2-[(3-aminopropyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (dissolved in pyridine (5 mL) To 1,3-benzodioxol-5-yl) ethyl] acetamide (0.3 g, 0.7 mmol) (compound of formula (Yc6)) was added acetic anhydride (0.10 mL, 1.0 mmol). After stirring for 16 hours, the reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. Chromatography on silica with CH ₂ Cl ₂ gives 0.14 g of 2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl ] Amino] -N- [2- (1,3-benzodioxol-5-yl) ethyl] acetamide (compound of formula (Yc7)) was obtained;

A compound of formula (Yc7) and its derivatives are suitably substituted starting materials

2-[[3- (methylsulfonylamino) propyl] [2- (lH-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3 -Benzodioxol-5-yl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, 3-benzodioxol-5-yl) ethyl] acetamide;

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-meth Methoxyphenyl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4- Methoxyphenyl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, 4-benzodioxane-6-yl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide;

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4 -Benzodioxane-6-yl) ethyl] acetamide;

2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide;

2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl] acetamide;

및

And

2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3 -Dihydrobenzofuran-5-yl) ethyl] acetamide;

Prepared in a similar manner.

2-[(3-aminopropyl) [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4- in pyridine (1.5 mL) To methoxyphenyl) ethyl] acetamide (135 mg, 0.32 mmol) (compound of formula (Yc6)) was added an aqueous solution of potassium cyanide (64 mg, 0.76 mmol) (1.5 mL). The mixture was stirred and heated to 80 ° C. overnight in an oil bath. The mixture was poured into water and extracted with ethyl acetate (three times 20 ml). The combined ethyl acetate fractions were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica (9: 1 CH ₃ CN / NH ₄ 0H) to give 2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6 -Methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl) ethyl] acetamide (compound of formula (Yc9)) was obtained as a white solid;

A compound of formula (Yc9) and its derivatives are suitably substituted starting materials

2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide;

및

And

2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide;

Prepared in a similar manner.

Scheme 4 illustrates another method for preparing a compound of formula (Yc). Compounds of formula (Ya) and formula (Yb) can be prepared analogously.                 

Compounds of formula (Yc10) were prepared by the methods disclosed herein. R ¹ , R ² , m and n are each independently as described in the Summary of the Invention for the compounds of Formula (Ya), Formula (Yb) and Formula (Yc); R ⁵ and W are also as described in the above summary of the compounds of the formulas (Ya), (Yb) and (Yc).

The synthesis may also be carried out as follows:

2-[[3-[(1,3-benzodioxol-5-ylmethyl) amino] (methyl) propyl] [2- (1H-imidazol-1-yl)-dissolved in THF (50 mL)- To 6-methylpyrimidin-4-yl] amino] acetic acid, ethyl ester (2.2 g, 4.6 mmol) (compound of formula (Yc10)), LiOH (0.34 g, 8.1 mmol) and water (10 mL) were added. After stirring for 16 hours, the solvent was removed in vacuo and 1N HCl (8.1 mL, 8.1 mmol) was added. The solvent was removed in vacuo to yield 2-[[3-[[(1,3-benzodioxol-5-ylmethyl) (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6 -Methylpyrimidin-4-yl] amino] acetic acid (compound of formula (Yc11)) was obtained.

2-[[3-[(1,3-benzodioxol-5-ylmethyl) (methyl) amino] propyl] [2- (1H-imidazol-1-yl) slurried in DMF (5 mL) Carbonyldiimidazole (0.14 g, 0.8 mmol) was added to -6-methylpyrimidin-4-yl] amino] acetic acid (0.35 g, 0.8 mmol) (compound of formula (Yc11)). After stirring for 20 minutes, diethylamine (0.25 mL, 2.4 mmol) was added. After stirring for 18 hours, the reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and dried (Na ₂ SO ₄ ), and then the solvent was removed in vacuo to give 0.91 g of the desired product. Chromatography on silica with CH ₂ Cl ₂ / MeOH gives 2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H- Imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N, N-diethylacetamide;

The compounds of formula (Yc12) and their derivatives were prepared in a similar manner:

2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] -N- (2-dimethylaminoethyl) acetamide;

및

And

2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] acetamide;

* * * * *

While the present invention has been described in terms of specific embodiments, those skilled in the art should understand that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention. In addition, specific situations, materials, compositions of matter, processes, and processing step (s) may be modified to suit the purposes, spirit, and scope of the present invention. All such modifications are intended to be included within the scope of the claims appended hereto.

Claims (15)

Compounds of formula (Ya), formula (Yb) or formula (Yc) as single stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof. <Formula Ya>

<Formula Yb>

<Formula Yc>

Where n and m are independently an integer from 1 to 4, A is -C (O) OR ¹ or -C (O) N (R ¹ ) R ² , W is N or CH, respectively, Each R ¹ is independently hydrogen, C ₁ -C ₈ alkyl, aryl or aryl C ₁ -C ₈ alkyl, Each R ² independently represents a hydrogen atom selected from hydrogen, C ₁ -C ₂₀ alkyl, — (CH ₂ ) _n —N (R ¹ ) ₂ , a carbon atom and 1 to 5 nitrogen, oxygen and sulfur; Containing 3- to 15-membered heterocyclyl C ₁ -C ₈ alkyl (unsubstituted or substituted by C ₁ -C ₈ alkyl, halo, halo C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy) or aryl C ₁ -C ₈ alkyl (unsubstituted or substituted by halo, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy or —N (R ¹ ) ₂ ), R ⁴ is hydroxy, -N (R ¹ ) R ² , -N (R ¹ ) -C (O) -R ¹ , -N (R ¹ ) -C (O when m is an integer from 2 to 4; ) OR ¹ , -N (R ¹ ) -S (O) _t -R ¹ or -N (R ¹ ) -C (O) -N (R ¹ ) ₂ , where m is an integer from 1 to 4 May also be cyano or 3- to 15-membered heterocyclyl containing a carbon atom and a heteroatom selected from the group consisting of 1 to 5 nitrogen, oxygen and sulfur, R ⁵ is hydrogen, halo, C ₁ -C ₈ alkyl, aryl, aryl C ₁ -C ₈ alkyl or halo C ₁ -C ₈ alkyl, Aryl means a phenyl group or a naphthyl group. The compound of claim 1, wherein n is 1; m is 2 or 3; A is —C (O) OR ¹ or —C (O) N (R ¹ ) R ² ; Each W is CH; R ¹ is hydrogen or C ₁ -C ₈ alkyl; R ² is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, — (CH ₂ ) _n —N (R ¹ ) ₂ , substituted or unsubstituted carbon atoms and 1 to 5 nitrogen, oxygen and sulfur A compound of formula (Yc) which is 3- to 15-membered heterocyclyl C ₁ -C ₈ alkyl containing heteroatoms, or substituted or unsubstituted aryl C ₁ -C ₈ alkyl. The compound of claim 2, wherein R ⁴ is —N (R ¹ ) R ² , wherein R ¹ is hydrogen or C ₁ -C ₈ alkyl and R ² is (1,3-benzodioxol-5-yl) methyl And (1,4-benzodioxane-6-yl) methyl containing from 1 to 4 carbon atoms and heteroatoms selected from the group consisting of 1 to 5 nitrogen, oxygen and sulfur. A compound which is a heteroaryl cyclic C ₁ -C ₈ alkyl. The method of claim 3, 2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] acetic acid, ethyl ester; 2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] -N, N-diethylacetamide; 2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] -N- (2-dimethylaminoethyl) acetamide; 2-[[3-[[(1,3-benzodioxol-5-yl) methyl] (methyl) amino] propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidine- 4-yl] amino] acetamide; 2-[[3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N, N-diethylacetamide; 2-[[3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N-methylacetamide; 2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N-methylacetamide; 2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino ] -N, N-diethylacetamide; 2-[[3-[(1,4-benzodioxan-6-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino Acetamide; And 2-[[(3-[(1,3-benzodioxol-5-yl) methyl] aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] Amino] acetamide. The compound of claim 2, wherein R ⁴ is a 3- to 15-membered heterocyclyl containing a carbon atom and a heteroatom selected from the group consisting of 1 to 5 nitrogens, oxygen and sulfur. The method of claim 5, 2-[[pyridin-3-ylmethyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodi Oxol-5-yl) ethyl] acetamide; 2-[[2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] [(1,3-benzodioxol-5-yl) methyl] amino] -N- [2 -(1,3-benzodioxol-5-yl) ethyl] acetamide; And 2-[[2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] [2- (morpholin-4-yl) ethyl] amino] -N- [2- (1 , 3-benzodioxol-5-yl) ethyl] acetamide. The compound of claim 2, wherein R ⁴ is hydroxy, cyano, -N (R ¹ ) R ² , -N (R ¹ ) -C (O) -R ¹ , -N (R ¹ ) -C (O) OR ¹ , -N (R ¹ ) -S (O) _t -R ¹ or -N (R ¹ ) -C (O) -N (R ¹ ) ₂ , where each R ¹ and each R ² is Independently hydrogen, C ₁ -C ₈ alkyl or aryl C ₁ -C ₈ alkyl. The method of claim 7, wherein 2-[[3-hydroxypropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol -5-yl) ethyl] acetamide; 2-[[2-cyanoethyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol -5-yl) ethyl] acetamide; 2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzo Dioxol-5-yl) ethyl] acetamide; 2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzo Dioxol-5-yl) ethyl] acetamide; 2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3 -Benzodioxol-5-yl) ethyl] acetamide; 2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, 3-benzodioxol-5-yl) ethyl] acetamide; 2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3- Benzodioxol-5-yl) ethyl] acetamide; 2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,3-benzodioxol- 5-yl) ethyl] acetamide; 2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl) ethyl] Acetamide; 2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-meth Methoxyphenyl) ethyl] acetamide; 2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4- Methoxyphenyl) ethyl] acetamide; 2-[[(3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-meth Methoxyphenyl) ethyl] acetamide; 2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide; 2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzodioxane- 6-yl) ethyl] acetamide; 2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1, 4-benzodioxane-6-yl) ethyl] acetamide; 2-[[3- (di (phenylmethyl) amino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1 , 4-benzodioxane-6-yl) ethyl] acetamide; 2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide; 2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4 -Benzodioxane-6-yl) ethyl] acetamide; 2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide; 2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide; 2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (4-methoxyphenyl ) Ethyl] acetamide; 2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4- Benzodioxan-6-yl) ethyl] acetamide; 2-[[3- (phenylmethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3- Dihydrobenzofuran-5-yl) ethyl] acetamide; 2-[[3-aminopropyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-dihydrobenzofuran -5-yl) ethyl] acetamide; 2-[[3- (dimethylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide; 2-[[3- (acetylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide; 2-[[3- (methoxycarbonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl] acetamide; 2-[[3- (methylsulfonylamino) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3 -Dihydrobenzofuran-5-yl) ethyl] acetamide; 2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (1,4-benzo Dioxane-6-yl) ethyl] acetamide; And 2-[[3- (ureido) propyl] [2- (1H-imidazol-1-yl) -6-methylpyrimidin-4-yl] amino] -N- [2- (2,3-di Hydrobenzofuran-5-yl) ethyl] acetamide. delete delete delete delete delete delete delete